Integrating Navigation-Assisted Ablation in the Locoregional Treatment of Hepatocellular Carcinoma

This case-control study investigates the association of navigation-assisted ablation with rate of incomplete ablations in patients with hepatocellular carcinoma.


Introduction
4][5] Ablative therapies have evolved over the last 2 decades, showing promise as a robust alternative to surgical resection in select patients. 6,7ndomized clinical trials report similar outcomes between surgical resection and RFA, with RFA treatment being less invasive and resulting in shorter hospital stays. 8,91][12][13] However, an ongoing challenge for ablative therapies involves the technical learning curve for precise localization of the tumor and accurate placement of the device to ensure complete ablation of the lesion while minimizing damage to surrounding structures. 14,15veral imaging modalities, including ultrasonography, magnetic resonance imaging (MRI), computed tomography (CT), and fluoroscopy, are actively used to target ablative therapies for HCC. 16The concomitant use of CT or MRI guidance is primarily available in the radiology suite and often inaccessible in the operative environment.Thus, many surgical teams use intraoperative ultrasonography to identify the tumor and assist with targeting the ablation probe.However, this approach has technical challenges owing to ultrasonography resolution and anatomic constraints that can limit visualization and is ultimately highly dependent on user experience. 17,18With the requisite technical skills required to successfully ablate liver tumors, the introduction of navigation is an exciting development in this domain of minimally invasive surgery.Over the last decade, novel navigation technologies have been developed as an adjunct to intraoperative ultrasonography. 19is study analyzes the use of navigation as an adjunct to intraoperative ultrasonography in liver cancer ablation.We hypothesized that the use of navigation would be associated with increased accuracy, a lower rate of incomplete ablations, and thus improved progression-free survival (PFS) compared with the same procedure done without navigation.With the increasing prevalence of HCC disease, ablative therapies for HCC are a vital surgical treatment associated with increased survival at the population level, and navigation is a tool that has the potential for associated increases in accuracy and accessibility of ablation.

Methods
This case-control study was reviewed by the University of North Carolina Institutional Review Board and approved to operate under a waiver of informed consent because the research involved no more than minimal risk to study participants and could not be practically carried out without the waiver.
This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline as published.

JAMA Network Open | Surgery
Navigation-Assisted Ablation in Locoregional Treatment of Hepatocellular Carcinoma

Study Design
This is a single-center, retrospective case-control study of a prospectively collected dataset of 757 adult patients (aged Ն18 years) with underlying liver disease who were treated with thermal ablation for HCC at a quaternary academic medical center between June 2001 and January 2021.Study participants were restricted to the time when navigation was introduced at the center (beginning in June 2011).Patient demographics, clinical and pathologic characteristics, and survival were extracted from the electronic health record (EHR).Patient race and ethnicity were identified in the EHR as Asian or Pacific Islander, Hispanic, Native American, non-Hispanic Black, and non-Hispanic White.
These were included in the analysis given that there are potential differences in the stage of tumor presentation by race.Data were extracted by a single reviewer (Y.I.) and confirmed by the senior author (D.A.G.).Participants were grouped by whether navigation was used during the ablation.
Missing data were assumed to be missing completely at random, thus missingness was assumed to have no effect on results and was ignored in the analysis.

Surgical Procedure
All procedures were laparoscopic and performed by a single surgeon (D.A.G.) experienced in minimally invasive hepatic surgery.This surgeon has more than 25 years of hepatobiliary surgery experience and more than 20 years of experience performing laparoscopic-assisted liver ablations.
The surgeon has incorporated intraoperative navigation for laparoscopic ablation for more than a decade.The comprehensive surgical experience in its entirety includes 1200 tumors treated in more than 750 patients.
All tumors were localized with intraoperative ultrasonography and compared with preoperative MRI or CT scans to confirm location.Lesion number and diameter noted in preoperative imaging were confirmed intraoperatively.MWA procedures were performed with 2 systems.The initial system involved a single or double antenna for the ablation with a power of 45 W for 8 to 10 minutes using a 915-Hz microwave generator (NeuWave System, Ethicon) as per established recommendations.Subsequent MWAs were performed with a 2.45-GHz, 13-G microwave antenna (Emprint SX, Medtronic).The generator was set between 45 and 100 W, and treatment occurred for 5 to 10 minutes based on the projected size of the ablation zone.Track coagulation was used at the end of each treatment.An optimal zone of ablation created a 0.5 to 1.0 cm margin of treated tissue around the tumor.

Navigation
The Emprint SX Ablation Platform with Thermosphere Technology uses an electromagnetic field generator placed under the patient and spatial sensors to track the location and orientation of the ablation antenna and ultrasonography probe.The antenna sensor is embedded in the antenna shaft itself, and the ultrasonography sensors are clipped onto the head of the ultrasonography probe.
Relative instrument locations are rendered as a real-time augmented reality image providing additional spatial information.Reference ablation volumes are derived from planned wattage and duration of ablation.These can be projected on the ultrasonography image to visualize and plan for the size, position, and extent of the ablation zone before it is initiated.Volumes are based on preclinical in vivo animal models.Targeting requires the user to aim the antenna at the location identified in the ultrasonography image.A small, green circle illuminates the antenna's projected path to the target on the ultrasonography plane.Once the image of the antenna is lined up, the user advances the antenna to the target.This 3-dimensional, real-time spatial data allows the surgeon to predetermine and approach a target from various out-of-plane paths and subsequently advance with line-of-sight trajectory (Video).

Statistical Analysis
The primary outcome of interest was the rate of incomplete ablations.Secondary outcomes included PFS, overall survival (OS), and operative time.Patient, disease, and treatment characteristics are Crude 5-year OS and PFS were estimated using the Kaplan-Meier method, and differences between groups were tested using the log-rank test.The Kaplan-Meier method is a nonparametric maximum likelihood estimator of the survival function for censored data.This analysis produces survival curves in the postoperative period, which shows the estimated survival probability for each time by group on the y-axis and follow-up time intervals on the x-axis.Data for all cases were used in this analysis until the end of follow-up or occurrence of the event of interest (recurrence or death).

JAMA Network Open | Surgery
Cox proportional hazards models were used to estimate hazard ratios (HRs) for associations between independent factors and OS and PFS.The Cox proportional hazard model is a semiparametric maximum likelihood regression method for assessing associations between 1 or more factors hypothesized to be associated with the outcome and survival time to events of interest (recurrence or death).All independent factors in all models were selected a priori based on clinical knowledge and experience.
A nominal significance level of .05 was used for all statistical tests.Statistical analyses were conducted using SAS statistical software version 9.4 (SAS Institute).Data were analyzed from October 2022 through June 2023.

Patient Characteristics
From the initial set of 757 total records, 666 patients met criteria for potential inclusion.1).

Tumor Characteristics
Tumor characteristics for patients undergoing ablation with and without navigation are summarized in Table 2.The overall cohort had a mean (SD) total bilirubin level of 1.6 (1.3) mg/dL, albumin level of 3.5 (0.6) g/dL, international normalized ratio of 1.2 (0.2) seconds, platelet count of 117.6 (68.1) × 10 9 /L, and creatinine level of 0.9 (0.4) mg/dL (  reported in eTable 3 in Supplement 1.There were no statistically significant differences in recurrence rates or incomplete ablation rates among patients undergoing ablations with vs without navigation, irrespective of whether the lesion was in a challenging location.We defined challenging location based on liver segments, with segment 6 being a moderately challenging location due to dysmorphic features of the cirrhotic liver and its location next to the abdominal wall and segments 7 and 8 being the most challenging location due to their cephalad and posterior anatomy.Among patients with lesions in segments 1 to 5, there was a statistically significant difference in rates of death among patients undergoing ablation with vs without navigation; however, this difference was not appreciable when challenging segments were expanded to include segment 6.
There were no differences in incomplete ablation rates (10 patients [9.2%] vs 10 patients

Clinical Outcomes
Clinical outcomes among patients who underwent ablation with and without navigation are summarized in eTable 4 in Supplement 1.A total of 79 patients (16.9%) underwent orthotopic liver transplant after ablation.The study cohort readmission rate was 18 of 205 patients (8.8%) with readmission data.The overall recurrence rate was 195 patients (41.8%) with recurrence data, and 169 patients (36.2%) were deceased at the time of data collection.The rate of recurrence trended downward over the study period (eFigure 2 in Supplement 1).

Discussion
This case-control study assessed the association of real-time ultrasonography-augmented navigation for HCC ablation with patient survival, operative time, and rate of incomplete ablations.
Intraoperative navigation was associated with comparable patient survival outcomes in patients who did not undergo navigation despite being performed in higher-stage HCC disease and anatomically challenging liver segments (eg, segments 6-8). 20,21Intraoperative time was longer for patients undergoing ablation with navigation, but rates of incomplete ablations were similar among patients who did vs did not receive navigation assistance.These findings complement the existing literature on the use of ablation in the treatment of hepatic tumors. 22 our knowledge, this study is the first of its kind to compare the integration of navigation with laparoscopic-assisted ablation of HCC.The potential implications for the role of intraoperative navigation in treating anatomically challenging liver tumors is far reaching.The current literature on navigation integration with laparoscopic ablation is limited.In a 2022 study by Ohama et al, 23 the use of ultrasonography-guided RFA for initial recurrence of early-stage HCC was reported to be of equal therapeutic efficacy compared with resection.Our study's finding of a comparable rate of recurrence   One of the challenges with laparoscopic ablation of liver tumors is the difficulty in locating lesions in difficult-to-reach anatomical locations of the liver.In this study, tumors located in the dome (eg, segments 7 and 8) were more readily accessed via navigation.The advantage of navigation assistance may be more pronounced when surgeons are still relatively new to laparoscopic ablation.
The steep learning curve for laparoscopic liver tumor ablation is well documented and remains a barrier for broad adoption of the technique, despite its potential benefits. 15The learning curve for laparoscopic ablation ranges from approximately 50 to 93 cases to reach significant reductions in an incomplete ablation rate for malignant liver tumors 15,24,25 ; however, literature on how navigation affects this learning curve is lacking.While measuring the learning curve was outside the scope of this study, the overall downtrend in rates of incomplete ablations and recurrences seen over our study period suggest that navigation may allow for a shorter learning curve.In addition to dedicated training, the incorporation of navigation into laparoscopic ablation training may help flatten the learning curve, leading to broader adoption.
We initially hypothesized that incorporating navigation would be associated with improved targeting accuracy, with a lower rate of incomplete ablations compared with the same procedure done without navigation.This hypothesis was not supported by results, and we suspect that the lack of change in the rate of incomplete ablations was associated with several factors.First, the surgeon performing the procedure had more than a decade of experience with laparoscopic ablations when navigation technology was introduced.At this point in the surgeon's experience, there may be less benefit to gain in targeting accuracy, and it was challenging to control for this human-factor in the study.Another factor that may be contributing to the lack of an association with incomplete ablations is selection bias.Tumors that were preoperatively identified as being in an accessible location did not routinely have navigation technology incorporated in the case at the study institution, thus

[ 10 .
5%]; P = .32)or tumor size among patients undergoing ablation with vs without navigation.The overall rate of incomplete ablations trended downward over the course of the study (eFigure 2 in Supplement 1).

Figure 2 .No
Figure 2. Kaplan-Meier Plot for 5-y Recurrence-Free Survival Navigation-Assisted Ablation in Locoregional Treatment of Hepatocellular Carcinoma JAMA Network Open.2024;7(2):e240694.doi:10.1001/jamanetworkopen.2024.0694(Reprinted) February 29, 2024 3/12 Downloaded from jamanetwork.comby guest on 03/07/2024 summarized with median (IQR) or mean (SD) for continuous variables and number (percentage) for categorical variables by navigation use.Differences between groups (navigation vs no navigation) were tested using the Wilcoxon rank sum test for continuous variables and the χ 2 or Fisher exact test for categorical variables.Normality tests (Shapiro-Wilk test and visual inspection of histograms) were conducted to determine if nonparametric methods were appropriate for between-group comparisons of continuous variables.The Shapiro-Wilk test checks for normality assumption using W statistics, which are positive and less than or equal to 1. Small values of W less than 0.05 indicate nonnormal distribution.

Table 3 .
Female sex was associated with a lower despite differences in tumor stage and location suggests that navigation may fill a unique and important gap in treating HCC among patients who are not candidates for surgical resection.

Table 3 .
Risk of Recurrence, Controlling for Liver Transplant and Death as Competing Risks (N = 467) Rates of Recurrence, Death, and Incomplete Ablations eFigure 2. Rates of Incomplete Ablations and Recurrences by Year eTable a Comparison involved patients who were in the initial total pool but not in the analysis set because navigation was introduced after these ablation systems were no longer in use.SUPPLEMENT 1. eFigure 1. Flowchart of Patient Inclusion in the Study eTable 1. Tumor Locations and Incomplete Ablation Rates eTable 2. Operative Times eTable 3.